HIGHLIGHTS OF PRESCRIBING INFORMATION ... · INTERMEZZO and of other concomitant CNS depressants...

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INTERMEZZO reg safely and effectively See full prescribing information for INTERMEZZO

INTERMEZZO reg (zolpidem tartrate) sublingual tablets CIV Initial US Approval 1992

WARNING COMPLEX SLEEP BEHAVIORS See full prescribing information for complete box warning

Complex sleep behaviors including sleep-walking sleep-driving and engaging in other activities while not fully awake may occur following use of INTERMEZZO Some of these events may result in serious injuries including death Discontinue INTERMEZZO immediately if a patient experiences a complex sleep behavior (4 51)

----------------------------RECENT MAJOR CHANGES-------------------------shyBox Warning 082019 Contraindications (4) 082019 Warnings and Precautions Complex Sleep Behaviors (51) 082019 Warnings and Precautions CNS Depressant Effects and Next-Day Impairment (52) 022019

---------------------------INDICATIONS AND USAGE---------------------------shyINTERMEZZO is a GABAA agonist indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep (1)

Limitation of Use Not indicated for the treatment of middle-of-the night awakening when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking (1)

-------------------------DOSAGE AND ADMINISTRATION-------------------shybull Take only if 4 hours of bedtime remain before the planned time of

waking (21 51) bull INTERMEZZO should be placed under the tongue and allowed to

disintegrate completely before swallowing The tablet should not be swallowed whole (21)

bull The effect of INTERMEZZO may be slowed if taken with or immediately after a meal (21)

bull Recommended dose is 175 mg for women and 35 mg for men taken only once per night if needed (22)

bull Lower doses of CNS depressants may be necessary when taken concomitantly with INTERMEZZO (23)

bull Co-administration with CNS depressants Recommended dose is 175 mg for men and women (23)

bull Geriatric patients and patients with hepatic impairment Recommended dose is 175 mg for men and women (24 25)

--------------------------DOSAGE FORMS AND STRENGTHS----------------shy175 mg and 35 mg sublingual tablets (3)

--------------------------------CONTRAINDICATIONS---------------------------shybull Patients who have experienced complex sleep behaviors after taking

INTERMEZZO (4 51) bull Known hypersensitivity to zolpidem (4)

---------------------------WARNINGS AND PRECAUTIONS-------------------shybull CNS depressant effects Impairs alertness and motor coordination

including risk of morning impairment Risk increases with dose and use with other CNS depressants and alcohol Instruct patients on correct use (52)

bull Evaluate for co-morbid diagnoses Re-evaluate if insomnia persists after 7 to 10 days of use (52)

bull Severe anaphylacticanaphylactoid reactions Angioedema and anaphylaxis have been reported Do not re-challenge if such reactions occur (53)

bull Abnormal Thinking and Behavioral Changes Changes including decreased inhibition bizarre behavior agitation and depersonalization have been reported Immediately evaluate any new onset behavioral changes (55)

bull Depression Worsening of depression or suicidal thinking may occur Prescribe the least number of tablets feasible to avoid intentional overdose (56)

bull Respiratory Depression Consider this risk before prescribing in patients with compromised respiratory function (57)

------------------------------ADVERSE REACTIONS--------------------------shyMost commonly observed adverse reactions (gt 1 in adult patients) are headache nausea and fatigue (61)

To report SUSPECTED ADVERSE REACTIONS contact Purdue Pharma at 1-888-726-7535 or FDA at 1-800-FDA-1088 or httpwwwfdagovmedwatch

-------------------------------DRUG INTERACTIONS-------------------------shybull CNS depressants including alcohol Possible adverse additive CNS

depressant effects (51 71) bull Imipramine Decreased alertness observed (71) bull Chlorpromazine Impaired alertness and psychomotor performance

observed (71) bull Rifampin Combination use may decrease effects (72) bull Ketoconazole Combination use may increase effects (72)

--------------------------USE IN SPECIFIC POPULATIONS----------------shybull Pregnancy Based on animal data zolpidem may cause fetal harm (81) bull Pediatric use Safety and effectiveness of INTERMEZZO not

established With bedtime dosing of zolpidem hallucinations observed (incidence 7) (84)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised 082019

Reference ID 4478947

FULL PRESCRIBING INFORMATION CONTENTS WARNING COMPLEX SLEEP BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

21 Important Administration Instructions 22 Basic Dosing Information 23 Use with CNS Depressants 24 Use in Geriatric Patients 25 Use in Patients with Hepatic Impairment

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

51 Complex Sleep Behaviors 52 CNS Depressant Effects and Next-Day Impairment 53 Need to Evaluate for Co-Morbid Diagnoses 54 Severe Anaphylactic and Anaphylactoid Reactions 55 Abnormal Thinking and Behavioral Changes 56 Use in Patients with Depression 57 Respiratory Depression 58 Withdrawal Effects

6 ADVERSE REACTIONS 61 Clinical Trials Experience

7 DRUG INTERACTIONS 71 CNS-active Drugs 72 Drugs that Affect Drug Metabolism via Cytochrome P450

8 USE IN SPECIFIC POPULATIONS

81 Pregnancy 83 Nursing Mothers 84 Pediatric Use 85 Geriatric Use 86 Gender Differences in Pharmacokinetics

9 DRUG ABUSE AND DEPENDENCE 91 Controlled Substance 92 Abuse 93 Dependence

10 OVERDOSAGE 101 Signs and Symptoms 102 Recommended Treatment

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

121 Mechanism of Action 123 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 131 Carcinogenesis Mutagenesis Impairment of Fertility

14 CLINICAL STUDIES 141 Middle-of-the-Night Awakening Trials 142 Special Safety Studies

16 HOW SUPPLIEDSTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the Full Prescribing Information are not listed


FULL PRESCRIBING INFORMATION

WARNING COMPLEX SLEEP BEHAVIORS

Complex sleep behaviors including sleep-walking sleep-driving and engaging in other activities while not fully awake may occur following use of INTERMEZZO Some of these events may result in serious injuries including death Discontinue INTERMEZZO immediately if a patient experiences a complex sleep behavior [see Contraindications (4) and Warnings and Precautions (51)]

1 INDICATIONS AND USAGE INTERMEZZO reg (zolpidem tartrate) sublingual tablet is indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep

Limitations of Use INTERMEZZO is not indicated for the treatment of middle-of-the-night insomnia when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking

2 DOSAGE AND ADMINISTRATION

21 Important Administration Instructions INTERMEZZO is to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep INTERMEZZO should only be taken if the patient has at least 4 hours of bedtime remaining before the planned time of waking [see Warnings and Precautions (51)]

INTERMEZZO should be placed under the tongue and allowed to disintegrate completely before swallowing The tablet should not be swallowed whole For optimal effect INTERMEZZO should not be administered with or immediately after a meal The tablet should be removed from the pouch just prior to dosing

22 Basic Dosing Information The recommended and maximum dose of INTERMEZZO is 175 mg for women and 35 mg for men taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep The recommended doses for women and men are different because women clear zolpidem from the body at a lower rate than men [see Use in Specific Populations (86)]

23 Use with CNS Depressants The recommended INTERMEZZO dose for men and women who are taking concomitant CNS depressants is 175 mg Dose adjustment of concomitant CNS depressants may be necessary when co-administered with INTERMEZZO because of potentially additive effects The use of


INTERMEZZO with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Warnings and Precautions (51)]

24 Use in Geriatric Patients Geriatric patients may be especially sensitive to the effects of zolpidem The recommended dose of INTERMEZZO in men and women over 65 years old is 175 mg taken only once per night if needed [see Use in Specific Populations (85)]

25 Use in Patients with Hepatic Impairment The recommended dose of INTERMEZZO INTERMEZZO in patients with hepatic impairment is 175 mg taken only once per night if needed [see Clinical Pharmacology (123)]

3 DOSAGE FORMS AND STRENGTHS INTERMEZZO INTERMEZZO is available as 175 mg and 35 mg tablets for sublingual administration

INTERMEZZO INTERMEZZO 175 mg tablets are yellow round uncoated biconvex debossed with ZZ on one side

INTERMEZZO INTERMEZZO 35 mg tablets are beige round uncoated biconvex debossed with ZZ on one side

4 CONTRAINDICATIONS INTERMEZZO is contraindicated in patients who have experienced complex sleep behaviors after taking INTERMEZZO [see Warnings and Precautions (51)]

INTERMEZZO is contraindicated in patients with known hypersensitivity to zolpidem Observed reactions with zolpidem include anaphylaxis and angioedema [see Warnings and Precautions (54)]

5 WARNINGS AND PRECAUTIONS 51 COMPLEX SLEEP BEHAVIORS

Complex sleep behaviors including sleep-walking sleep-driving and engaging in other activities while not fully awake may occur following the first or any subsequent use of zolpidem Patients can be seriously injured or injure others during complex sleep behaviors Such injuries may result in a fatal outcome Other complex sleep behaviors (eg preparing and eating food making phone calls or having sex) have also been reported Patients usually do not remember these events Post-marketing reports have shown that complex sleep behaviors may occur with zolpidem alone at recommended dosages with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (71)] ] Discontinue INTERMEZZO immediately if a patient experiences a complex sleep behavior


52 CNS Depressant Effects and Next-Day Impairment INTERMEZZO like other sedative-hypnotic drugs has CNS depressant effects Co-administration with other CNS depressants (eg benzodiazepines opioids tricyclic antidepressants alcohol) increases the risk of CNS depression Dosage adjustments of INTERMEZZO and of other concomitant CNS depressants may be necessary when INTERMEZZO is administered with such agents because of the potentially additive effects The use of INTERMEZZO with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Dosage and Administration (23)]

In a driving study healthy subjects who received INTERMEZZO with fewer than four hours of bedtime remaining had evidence of impaired driving compared to subjects who received placebo [see Clinical Studies (142)] The risk of next-day driving impairment (and psychomotor impairment) is increased if INTERMEZZO is taken with less than 4 hours of bedtime remaining if higher than recommended dose is taken if co-administered with other CNS depressants or co-administered with other drugs that increase the blood levels of zolpidem

Because INTERMEZZO can cause drowsiness and a decreased level of consciousness patients particularly the elderly are at a higher risk of falls

53 Need to Evaluate for Co-morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical andor psychiatric disorder symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric andor medical illness that should be evaluated Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder Such findings have emerged during the course of treatment with sedative-hypnotic drugs including zolpidem

54 Severe Anaphylactic and Anaphylactoid Reactions Cases of angioedema involving the tongue glottis or larynx have been reported in patients after taking the first or subsequent doses of zolpidem Some patients have had additional symptoms such as dyspnea throat closing or nausea and vomiting that suggest anaphylaxis Some patients have required medical therapy in the emergency department If angioedema involves the throat glottis or larynx airway obstruction may occur and be fatal Patients who develop angioedema or anaphylaxis after treatment with zolpidem should not be rechallenged with INTERMEZZO

55 Abnormal Thinking and Behavioral Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including zolpidem Some of these changes included decreased inhibition (eg aggressiveness and extroversion that seemed out of character) bizarre behavior agitation and depersonalization Visual and auditory hallucinations have also been reported

In controlled trials of zolpidem tartrate 10 mg taken at bedtime lt 1 of adults with insomnia who received zolpidem reported hallucinations In a clinical trial 7 of pediatric patients treated with zolpidem tartrate 025 mgkg taken at bedtime reported hallucinations versus 0 treated with placebo [see Use in Specific Populations (84)]


The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation

56 Use in Patients with Depression In primarily depressed patients treated with sedative-hypnotics worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported Suicidal tendencies may be present in such patients and protective measures may be required Intentional overdosage is more common in this group of patients therefore the lowest number of tablets that is feasible should be prescribed for the patient at any one time

57 Respiratory Depression Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80 and 90 was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo Since sedative-hypnotics have the capacity to depress respiratory drive precautions should be taken if INTERMEZZO is prescribed to patients with compromised respiratory function Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate most of whom had pre-existing respiratory impairment have been reported The risks of respiratory depression should be considered prior to prescribing INTERMEZZO in patients with respiratory impairment including sleep apnea and myasthenia gravis

58 Withdrawal Effects There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem Monitor patients for tolerance abuse and dependence [see Drug Abuse and Dependence (92) and (93)]

6 ADVERSE REACTIONS The following serious adverse reactions in zolpidem-treated patients are discussed in greater detail in other sections of the labeling

bull Complex Sleep Behaviors [See Warnings and Precautions (51)]

bull CNS-Depressant Effects and Next-Day Impairment [See Warnings and Precautions (52)]

bull Serious Anaphylactic and Anaphylactoid Reactions [See Warnings and Precautions (52)]

bull Abnormal Thinking and Behavioral Changes [See Warnings and Precautions (55)]

bull Withdrawal Effects [See Warnings and Precautions (58)]


61 Clinical Trials Experience The safety data described below are based on two double-blind placebo-controlled trials of INTERMEZZO in adult patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening [see Clinical Studies (141)] These two trials included 230 and 82 patients treated with 35 mg and 175 mg of INTERMEZZO respectively The first study was a 3-way crossover sleep-laboratory study in 82 patients (58 female and 24 male median age 47 years 51 Caucasian 44 African-American) of 175 mg and 35 mg of INTERMEZZO compared to placebo (Study 1) The second study was a 4-week parallel-group at-home study in 295 patients (201 female and 94 male median age 43 years) of 35 mg of INTERMEZZO compared to placebo used on an as-needed basis after spontaneous middle-ofshythe-night awakenings (Study 2) In Study 2 patients took INTERMEZZO during the night on 62 of study nights

Because clinical trials are conducted under widely varying conditions adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in actual practice

Table 1 shows the incidence of adverse reactions reported in Study 2 that occurred in 2 or more of INTERMEZZO -treated (35 mg) patients in which the incidence was greater than the incidence in placebo-treated patients For women and other patients taking the 175 mg dose in Study 1 the incidence of adverse reactions was similar to the incidence seen with 35 mg of INTERMEZZO in Table 1

The most commonly reported adverse reactions in all treatment groups were headache nausea and fatigue

Table 1 Summary of Adverse Reactions (ge 2) in Outpatient Double-Blind Parallel-Group Placebo-Controlled Study (Study 2)

MedDRA System Organ Class Preferred Term 35 mg

INTERMEZZO (n=150)

Placebo (n=145)

Gastrointestinal Disorders 4 2 Nausea 1 1

General Disorders and Administration Site Conditions 3 0

Fatigue 1 0

Nervous System Disorders 5 3 Headache 3 1


7 DRUG INTERACTIONS

71 CNS-active Drugs Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (51 52)] Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs

Imipramine

Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20 decrease in peak levels of imipramine but there was an additive effect of decreased alertness Similarly chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction but there was an additive effect of decreased alertness and psychomotor performance

Haloperidol

A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration

Alcohol

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (51 52)]

Sertraline

Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamic effect of zolpidem

Fluoxetine

After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17) was observed There was no evidence of an additive effect in psychomotor performance [see Clinical Pharmacology (123)]

72 Drugs that Affect Drug Metabolism via Cytochrome P450 Some compounds known to inhibit CYP3A may increase exposure to zolpidem The effect of other P450 enzymes on the exposure to zolpidem is not known

Rifampin

Rifampin a CYP3A4 inducer significantly reduced the exposure to and the pharmacodynamic effects of zolpidem Use of rifampin in combination with zolpidem may decrease the efficacy of zolpidem

Ketoconazole

Ketoconazole a potent CYP3A4 inhibitor increased the pharmacodynamic effects of zolpidem Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together



81 Pregnancy Pregnancy Category C

There are no adequate and well-controlled studies of zolpidem in pregnant women Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted however cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy especially when taken with other CNS-depressants Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy INTERMEZZO should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring at doses greater than the recommended human dose (RHD) of 35 mgday (approximately 28 mgday zolpidem base) however teratogenicity was not observed

When zolpidem was administered at oral doses of 4 20 and 100 mg basekgday to pregnant rats during the period of organogenesis dose-related decreases in fetal skull ossification were observed at all but the lowest dose which is approximately 15 times the RHD on a mgm2 basis In rabbits treated during organogenesis with zolpidem at oral doses of 1 4 and 16 mg basekgday increased embryo-fetal death and incomplete fetal skull ossification were seen at the highest dose tested The no-effect dose for embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mgm2 basis Administration of zolpidem to rats at oral doses of 4 20 and 100 mg basekgday during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose which is approximately 15 times the RHD on a mgm2 basis

83 Nursing Mothers Zolpidem is excreted in human milk The effect of zolpidem on the nursing infant is not known

84 Pediatric Use INTERMEZZO is not recommended for use in children Safety and effectiveness of INTERMEZZO have not been established in pediatric patients below the age of 18

In an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD an oral solution of zolpidem tartrate dosed at 025 mgkg at bedtime did not decrease sleep latency compared to placebo Hallucinations were reported in 7 of the pediatric patients who received zolpidem none of the pediatric patients who received placebo reported hallucinations

85 Geriatric Use INTERMEZZO dosage adjustment is necessary in geriatric patients Sedating drugs may cause confusion and over-sedation in the elderly elderly patients generally should be started on low


doses of INTERMEZZO and observed closely [see Dosage and Administration (24) and Clinical Pharmacology (123)]

Clinical trial experience with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime

A total of 154 patients in US-controlled clinical trials and 897 patients in non-US clinical trials who received oral zolpidem were ge 60 years of age For a pool of US patients receiving oral zolpidem tartrate at doses of le 10 mg or placebo there were three adverse reactions occurring at an incidence of at least 3 for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (see Table 2)

Table 2 Adverse Reactions in Geriatric Patients in Pooled Trials of 5 mg to 10 mg of Oral Zolpidem Tartrate Given at Bedtime

Adverse Reaction 5 to 10 mg Oral Zolpidem tartrate

Placebo

Dizziness 3 0

Drowsiness 5 2

Diarrhea 3 1

Falls in geriatric patients

A total of 301959 (2) non-US patients receiving other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) reported falls including 2830 (93) who were ge 70 years of age Of these 28 patients 23 (82) were receiving zolpidem tartrate doses gt 10 mg A total of 241959 (1) non-US patients receiving zolpidem reported confusion including 1824 (75) who were ge70 years of age Of these 18 patients 14 (78) were receiving zolpidem tartrate doses gt10 mg

The dose of INTERMEZZO in elderly patients is 175 mg to minimize adverse effects related to impaired motor andor cognitive performance and unusual sensitivity to sedative-hypnotic drugs

86 Gender Difference in Pharmacokinetics Women cleared zolpidem tartrate from the body after sublingual administration of a 35 mg dose of INTERMEZZO at a lower rate than men (27 mLminkg vs 40 mLminkg) Cmax and AUC parameters of zolpidem were approximately 45 higher at the same dose in female subjects compared with male subjects Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose the recommended dose of INTERMEZZO for women is 175 mg and the recommended dose for adult men is 35 mg


9 DRUG ABUSE AND DEPENDENCE

91 Controlled Substance Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation

92 Abuse Abuse and addiction are separate and distinct from physical dependence and tolerance Abuse is characterized by misuse of the drug for non-medical purposes often in combination with other psychoactive substances Tolerance is a state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drug effects over time Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects

Addiction is a primary chronic neurobiological disease with genetic psychosocial and environmental factors influencing its development and manifestations It is characterized by behaviors that include one or more of the following impaired control over drug use compulsive use continued use despite harm and craving Drug addiction is a treatable disease using a multidisciplinary approach but relapse is common

Studies of abuse potential in former drug abusers found that the effects of single doses of 40 mg of oral zolpidem tartrate were similar but not identical to diazepam 20 mg while 10 mg of oral zolpidem tartrate was difficult to distinguish from placebo

Because persons with a history of addiction to or abuse of drugs or alcohol are at increased risk for misuse abuse and addiction of zolpidem they should be monitored carefully when receiving INTERMEZZO

93 Dependence Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation rapid dose reduction decreasing blood level of the drug andor administration of an antagonist

Sedative-hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps vomiting sweating tremors and convulsions The following adverse events which are considered to meet the DSMshyIII-R criteria for uncomplicated sedative-hypnotic withdrawal were reported during US clinical trials with other oral zolpidem formulations following placebo substitution occurring within 48 hours following the last zolpidem treatment fatigue nausea flushing lightheadedness uncontrolled crying emesis stomach cramps panic attack nervousness and abdominal discomfort These reported adverse events occurred at an incidence of 1 or less However available data cannot provide a reliable estimate of the incidence if any of dependence during treatment at recommended doses Post-marketing reports of abuse dependence and withdrawal resulting from use of oral zolpidem tartrate have been received


10 OVERDOSAGE

101 Signs and Symptoms In post-marketing experience of overdose with oral zolpidem tartrate alone or in combination with CNS-depressant agents impairment of consciousness ranging from somnolence to coma cardiovascular andor respiratory compromise and fatal outcomes have been reported

102 Recommended Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate Intravenous fluids should be administered as needed Zolpidemrsquos sedative-hypnotic effect was shown to be reduced by flumazenil and therefore flumazenil may be useful however flumazenil administration may contribute to the appearance of neurological symptoms (convulsions) As in all cases of drug overdose respiration pulse blood pressure and other appropriate signs should be monitored and general supportive measures employed Hypotension and CNS depression should be treated by appropriate medical intervention Sedating drugs should be withheld following zolpidem overdosage even if excitation occurs The value of dialysis in the treatment of overdosage has not been determined although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable

As with management of all overdosage the possibility of multiple drug ingestion should be considered The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage

11 DESCRIPTION INTERMEZZO contains zolpidem tartrate a non-benzodiazepine hypnotic of the imidazopyridine class INTERMEZZO is available in 175 mg and 35 mg strength tablets for sublingual administration INTERMEZZO sublingual tablets are intended to be placed under the tongue where they will disintegrate

INTERMEZZO sublingual tablets contain a bicarbonate-carbonate buffer

Chemically zolpidem tartrate is NN-6-trimethyl-2-p-tolylimidazo[12-α]pyridine-3-acetamide L-(+)-tartrate (21)

N

N

CH3

O

N

CH3

CH3

CH3

OHOH

O

OH

OH

O

2

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water alcohol and propylene glycol It has a molecular weight of 76488


Each INTERMEZZO tablet includes the following inactive ingredients mannitol sorbitol crospovidone silicon dioxide sodium carbonate sodium bicarbonate croscarmellose sodium sodium stearyl fumarate silicon dioxide natural and artificial spearmint flavor silicon dioxide-colloidal and sucralose The 175 mg tablet also contains yellow iron oxide and the 35 mg tablet contains beige iron oxide

12 CLINICAL PHARMACOLOGY

121 Mechanism of Action Zolpidem the active moiety of zolpidem tartrate is a hypnotic agent with a chemical structure unrelated to benzodiazepines barbiturates or other drugs with known hypnotic properties It interacts with a GABA-BZ complex and shares some of the pharmacological properties of the benzodiazepines In contrast to the benzodiazepines which nonselectively bind to and activate all BZ receptor subtypes zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1alpha5 subunits This selective binding of zolpidem on the BZ1

receptor is not absolute but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses

123 Pharmacokinetics Absorption

INTERMEZZO disintegrates in the sublingual cavity after administration On average INTERMEZZO is rapidly absorbed in both genders with a mean Tmax across studies of about 35 minutes to about 75 minutes

In healthy normal volunteers (age 21 to 45 years) dosed with 35 mg INTERMEZZO the average Cmax and AUC were 77 ngmL and 296 ngmiddothmL respectively in women The average Cmax and AUC were 53 ngmL and 198 ngmiddothmL respectively in men In women the average Cmax and AUC of the 175 mg INTERMEZZO dose were 37 ngmL and 151 ngmiddothmL respectively

Food decreased the overall Cmax and AUC of INTERMEZZO 35 mg by 42 and 19 respectively and increased the time to peak exposure (Tmax) to nearly 3 hours For optimal effect INTERMEZZO should not be administered with or immediately after a meal

Distribution

Based on data obtained with oral zolpidem the total protein binding was found to be 93 plusmn 01 and remained constant independent of concentration between 40 ngmL and 790 ngmL

Metabolism

Based on data obtained with oral zolpidem zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion

Elimination


The elimination half-life of a single dose of a 35 mg INTERMEZZO sublingual tablet is approximately 25 hours (range 14 to 36 hours)

Special Populations

Elderly The recommended dose for INTERMEZZO is 175 mg A pharmacokinetic study of 175 mg and 35 mg doses of INTERMEZZO showed that the plasma Cmax and AUC0-4 hr in elderly subjects following the 35 mg dose was higher by 34 and 30 respectively than the non-elderly subjects The Cmax and AUC of 175 mg in elderly subjects were consistently lower than those observed for the 35 mg dose in non-elderly subjects but consistently higher than the 175 mg dose in non-elderly subjects The elimination half-life remained unchanged

Hepatic Impairment The pharmacokinetics of oral zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in subjects with normal hepatic function Following a single 20 mg oral zolpidem tartrate dose mean Cmax and AUC were found to be two times (250 ngmL vs 499 ngmL) and five times (788 ngmiddothrmL vs 4203 ngmiddothrmL) higher respectively in hepatically compromised patients compared to subjects with normal hepatic function Tmax did not change The mean half-life in cirrhotic patients of 99 hr (range 41 to 258 hr) was greater than that observed in subjects with normal hepatic function of 22 hr (range 16 to 24 hr) Dosing should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration (25)]

Renal Impairment The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr= 65 plusmn 15 mLmin) undergoing hemodialysis three times a week who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days No statistically significant differences were observed for Cmax Tmax half-life and AUC between the first and last day of drug administration when baseline concentration adjustments were made Zolpidem was not hemodialyzable No accumulation of unchanged drug appeared after 14 or 21 days Zolpidem pharmacokinetics were not significantly different in renallyshyimpaired patients No dosage adjustment is necessary in patients with renal impairment

Drug Interactions

CNS-depressants

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (51)] Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20 decrease in peak levels of imipramine but there was an additive effect of decreased alertness Similarly chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction but there was an additive effect of decreased alertness and psychomotor performance


An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (51)]


Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses at 700 am in healthy female volunteers) zolpidem Cmax was significantly higher (43) and Tmax was significantly decreased (-53) Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem

A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions When multiple doses of zolpidem and fluoxetine were given at steady state and the concentrations evaluated in healthy females an increase in the zolpidem half-life (17) was observed There was no evidence of an additive effect in psychomotor performance

Drugs that Affect Drug Metabolism via Cytochrome P450

Some compounds known to inhibit CYP3A may increase exposure to zolpidem The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown

A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34 increase in AUC0- of zolpidem tartrate There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness postural sway or psychomotor performance

A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73) Cmax (-58) and T12

(-36 ) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate Rifampin a CYP3A4 inducer significantly reduced the exposure to and the pharmacodynamic effects of zolpidem

A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole a potent CYP3A4 inhibitor given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30) and the total AUC of zolpidem (70) compared to zolpidem alone and prolonged the elimination half-life (30 ) along with an increase in the pharmacodynamic effects of zolpidem Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together

Other Drugs with No Interactions with Zolpidem

A study involving cimetidinezolpidem tartrate and ranitidinezolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem

Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects

13 NONCLINICAL TOXICOLOGY

131 Carcinogenesis Mutagenesis Impairment of Fertility Carcinogenesis Zolpidem was administered in the diet to rats and mice for 2 years at doses of 4 18 and 80 mg basekgday In mice these doses are approximately 7 30 and 140 times respectively the recommended human dose (RHD) of 35 mgday (approximately 28 mg zolpidem base) on a mgm2 basis In rats these doses are approximately 15 60 and 280 times


respectively the RHD on a mgm2 basis No evidence of carcinogenic potential was observed in mice In rats renal tumors (lipoma liposarcoma) were seen at the mid- and high doses

Mutagenesis Zolpidem was negative in in vitro (bacterial reverse mutation mouse lymphoma and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays

Impairment of fertility Oral administration of zolpidem (doses of 4 20 and 100 mg basekgday) to rats prior to and during mating and continuing in females through postpartum day 25 resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose tested The no-effect dose for these findings is approximately 70 times the RHD on a mgm2 basis There was no impairment of fertility at any dose tested

14 CLINICAL STUDIES

141 Middle-of-the-Night Awakening Trials INTERMEZZO was evaluated in two randomized double-blind placebo-controlled studies (Studies 1 and 2) in patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night (MOTN) awakening In these studies patients met the diagnosis for primary insomnia as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and had at least three prolonged MOTN awakenings per week that were at least 30 minutes in duration

Sleep Laboratory Study (Scheduled Dosing) Adult patients aged 19 to 64 years (N=82 58 female 24 male) with a history of difficulty returning to sleep after middle-of-the-night awakenings were evaluated in a double-blind placebo-controlled 3-period cross-over sleep laboratory study (Study 1) The primary outcome measure was latency to persistent sleep (LPS) Doses of 35 mg and 175 mg of INTERMEZZO significantly decreased both objective (by polysomnography) and subjective (patient-estimated) sleep latency after a scheduled middle-ofshythe-night awakening as compared to placebo The effect on sleep latency was similar for females receiving 175 mg of INTERMEZZO and males receiving 35 mg of INTERMEZZO

Outpatient Study (As-needed Dosing)

Adult patients aged 18 to 64 years (N=295 201 women 94 men) with difficulty returning to sleep after middle-of-the-night awakenings were evaluated in a double-blind placebo-controlled 4-week outpatient study of INTERMEZZO Patients took study drug (35 mg of INTERMEZZO or placebo) on an as-needed (prn) basis when they had difficulty returning to sleep after waking in the middle of the night provided they had at least 4 hours time remaining in bed Subjective (patient-estimated) time to fall back to sleep after middle-of-the-night awakening was significantly shorter for INTERMEZZO 35 mg compared to placebo

142 Special Safety Studies Driving Study

A randomized double-blind placebo-controlled active-control single-center four-period crossover study in 40 healthy subjects was conducted to evaluate the effects of middle-of-the-


night administration of INTERMEZZO on next-morning driving performance The four randomized treatments included INTERMEZZO 35 mg four hours before driving INTERMEZZO 35 mg three hours before driving placebo and a positive control (an unapproved sedative-hypnotic) given nine hours before driving

The primary outcome measure was the change in the standard deviation of lateral position (SDLP) a measure of driving impairment The results were analyzed using a symmetry analysis which determined the proportion of subjects whose change from their own SDLP in the placebo condition was statistically significantly above a threshold thought to reflect clinically meaningful driving impairment

When driving began 3 hours after taking INTERMEZZO testing had to be terminated for one subject (a 23-year old woman) due to somnolence Overall the symmetry analysis showed a statistically significant impairing effect at 3 hours When driving began 4 hours after taking INTERMEZZO statistically significant impairment was not found but numerically INTERMEZZO was worse than placebo Zolpidem blood levels were not measured in the driving study and the study was not designed to correlate specific blood level with degree of impairment However the estimated blood level of zolpidem in patients whose SDLP worsened according to the symmetry analysis is considered to present a risk for driving impairment In some women the 35 mg dose of INTERMEZZO results in zolpidem blood levels that remain at or sometimes considerably above this level 4 or more hours after dosing Therefore the recommended dose for women is 175 mg A small negative effect on SDLP may remain in some patients 4 hours after the 175 mg dose in women and after the 35 mg dose in men such that a potential negative effect on driving cannot be completely excluded

Rebound effects

In studies performed with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime there was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg oral zolpidem tartrate

Memory impairment in controlled studies

Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration at bedtime of 5 mg to 10 mg oral zolpidem tartrate However in one study involving zolpidem tartrate doses of 10 mg and 20 mg there was a significant decrease in next-morning recall of information presented to subjects during peak drug effect (90 minutes post-dose) ie these subjects experienced anterograde amnesia There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of oral zolpidem tartrate predominantly at doses above 10 mg

16 HOW SUPPLIEDSTORAGE AND HANDLING Each sublingual tablet is individually packaged in a unit-dose pouch INTERMEZZO 175 mg


tablets are yellow round uncoated biconvex debossed with ZZ on one side and supplied as

NDC 59011-256-30 Carton of 30 unit-dose pouches

INTERMEZZO 35 mg tablets are beige round uncoated biconvex debossed with ZZ on one side and supplied as


Storage and Handling Store between 20degC to 25degC (68degF to 77degF) Excursions permitted between 15degC and 30degC (59degF and 86degF) Protect from moisture

The patient should be instructed not to remove the sublingual tablet from the unit-dose pouch until the patient is ready to consume it

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide)

Inform patients and their families about the benefits and risks of treatment with INTERMEZZO Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with INTERMEZZO and with each prescription refill Review the INTERMEZZO Medication Guide with every patient prior to initiation of treatment Instruct patients or caregivers that INTERMEZZO should be taken only as prescribed

Complex Sleep Behaviors

Instruct patients and their families that INTERMEZZO may cause complex sleep behaviors including sleep-walking sleep-driving preparing and eating food making phone calls or having sex while not being fully awake Serious injuries and death have occurred during complex sleep behavior episodes Tell patients to discontinue INTERMEZZO and notify their healthcare provider immediately if they develop any of these symptoms [see Boxed Warning Warnings and Precautions (51)]

CNS depressant Effects and Next-Day Impairment

Tell patients that INTERMEZZO has the potential to cause next-day impairment and that this risk is increased if dosing instructions are not carefully followed Tell patients to wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness Advise patients the increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (52)]

Severe Anaphylactic and Anaphylactoid Reactions


Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem Describe the signssymptoms of these reactions and advise patients to seek medical attention immediately if any of them occur [see Warnings and Precautions (54)]

Suicide

Tell patients to immediately report any suicidal thoughts

Administration Instructions

For detailed instructions on how to use INTERMEZZO tell patients to refer to the Patient Instructions for Use Tell patients that INTERMEZZO is to be taken only once per night if needed if they wake in the middle of the night and have difficulty returning to sleep Tell patients that INTERMEZZO should only be taken if they have 4 hours of bedtime remaining before the planned time of waking Instruct the patient to place the tablet under the tongue allowing it to disintegrate completely before swallowing Tell the patient that INTERMEZZO should not be swallowed whole Tell patients that the effect of INTERMEZZO may be slowed if taken with or immediately after a meal Instruct patients to remove the tablet from the unit-dose pouch just prior to dosing Advise patients NOT to take INTERMEZZO if they drank alcohol that day or before bed

Healthcare professionals can telephone Purdue Pharmarsquos Medical Services Department (1-888-726-7535) for information on this product

Distributed by Purdue Pharma LP Stamford CT 06901-3431 Manufactured by Patheon Pharmaceuticals Inc Cincinnati OH 45237

US Patent Numbers 7658945 7682628 8242131 8252809

copy2019 Purdue Pharma LP


MEDICATION GUIDE

INTERMEZZO reg (in ter meacutet zoh)

(zolpidem tartrate) sublingual tablet CIV

Read the Medication Guide that comes with INTERMEZZOreg before you start taking it and each time you get a refill There may be new information This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment

What is the most important information I should know about INTERMEZZO

Follow the Instructions for Use at the end of this Medication Guide when you take INTERMEZZO If you do not follow the Instructions for Use you might be drowsy in the morning without knowing it

bull Only take one tablet a night if needed

bull Only take INTERMEZZO if you have at least 4 hours of bedtime left

INTERMEZZO may cause serious side effects including

bull Complex sleep behaviors that have caused serious injury and death After taking INTERMEZZO you may get up out of bed while not being fully awake and do an activity that you do not know you are doing (complex sleep behaviors) The next


morning you may not remember that you did anything during the night These activities may occur with INTERMEZZO whether or not you drink alcohol or take other medicines that make you sleepy Reported activities include

o driving a car (sleep-driving)

o making and eating food

o talking on the phone

o having sex

o sleep-walking

Stop taking INTERMEZZO and call your healthcare provider right away if you find out that you have done any of the above activities after taking INTERMEZZO

Important

1 Take INTERMEZZO exactly as prescribed

2 Do not take INTERMEZZO if you

bull have ever experienced a complex sleep behavior (such as driving a car making and eating food talking on the phone or having sex while not fully awake) after taking Intermezzo

bull drank alcohol that day or before bed bull took another medicine to help you sleep bull do not have at least 4 hours of bedtime remaining

What is INTERMEZZO

INTERMEZZO is a sedative-hypnotic (sleep) medicine INTERMEZZO is used in adults for the treatment of a sleep problem called insomnia Many people have difficulty returning to sleep after awakening in the middle of the night INTERMEZZO is designed to specifically treat this problem

It is not known if INTERMEZZO is safe and effective in children

INTERMEZZO is a federally controlled substance (CIV) because it can be abused or lead to dependence Keep INTERMEZZO in a safe place to prevent misuse and abuse Selling or giving away INTERMEZZO may harm others and is against the law Tell your doctor if you have ever abused or have been dependent on alcohol prescription medicines or street drugs

Who should not take INTERMEZZO

bull Do not take INTERMEZZO if you have ever had a complex sleep behavior happen after taking INTERMEZZO

bull Do not take INTERMEZZO if you are allergic to zolpidem or any other ingredients in INTERMEZZO See the end of this Medication Guide for a complete list of ingredients in INTERMEZZO

bull Do not take INTERMEZZO if you have had an allergic reaction to drugs containing zolpidem such as Ambien Ambien CR Edluar or Zolpimist


Symptoms of a serious allergic reaction to INTERMEZZO can include

bull swelling of your face lips and throat that may cause difficulty breathing or swallowing

bull nausea and vomiting

INTERMEZZO may not be right for you Before starting INTERMEZZO tell your doctor about all of your health conditions including if you

bull have a history of depression mental illness or suicidal thoughts

bull have a history of drug or alcohol abuse or addiction

bull have kidney or liver disease

bull have a lung disease or breathing problems

bull are pregnant planning to become pregnant or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines vitamins and herbal supplements Medicines can interact with each other sometimes causing serious side effects Your doctor will tell you if you can take INTERMEZZO with your other medicines

Know the medicines you take Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine

How should I take INTERMEZZO

bull See ldquoWhat is the most important information I should know about INTERMEZZOrdquo

bull Read the ldquoInstructions for Userdquo at the end of this Medication Guide for detailed instructions on how to take INTERMEZZO

bull Take INTERMEZZO exactly as prescribed Only take one INTERMEZZO tablet per night if needed

bull Do not take INTERMEZZO if you drank alcohol that evening or before bed

bull While in bed place the tablet under your tongue and allow it to break apart completely Do not swallow it whole

bull You should not take INTERMEZZO with or right after a meal INTERMEZZO may help you fall asleep faster when you take it on an empty stomach

bull Call your health care provider if your insomnia worsens or is not better within 7 to 10 days This may mean that there is another condition causing your sleep problem

bull If you take too much INTERMEZZO or overdose get emergency treatment

What are the possible side effects of INTERMEZZO



bull getting out of bed while not being fully awake and doing an activity that you do not know you are doing (See ldquoWhat is the most important information I should know about INTERMEZZOrdquo)

bull abnormal thoughts and behavior Symptoms include more outgoing or aggressive behavior than normal confusion agitation hallucinations worsening of depression and suicidal thoughts or actions

bull memory loss

bull anxiety

bull severe allergic reactions Symptoms include swelling of the tongue or throat trouble breathing and nausea and vomiting Get emergency medical help if you get these symptoms after taking INTERMEZZO

Call your health care provider right away if you have any of the above side effects or any other side effects that worry you while using INTERMEZZO

The most common side effects of INTERMEZZO are

bull Headache

bull Nausea

bull Fatigue

Even if you follow the Instructions for Use you may still feel drowsy in the morning after taking INTERMEZZO Do not drive or do other dangerous activities after taking INTERMEZZO until you are fully awake

These are not all the side effects of INTERMEZZO Ask your health care provider or pharmacist for more information

You may report side effects to FDA at 1-800-FDA-1088

How should I store INTERMEZZO

bull Store INTERMEZZO at room temperature 68deg to 77degF (20deg to 25degC) Protect from moisture

bull Only open the pouch when you are ready to use INTERMEZZO

Keep INTERMEZZO and all medicines out of reach of children

General Information about INTERMEZZO

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide Do not use INTERMEZZO for a condition for which it was not prescribed Do not give INTERMEZZO to other people even if you think they have the same symptoms that you have It may harm them and it is against the law


This Medication Guide summarizes the most important information about INTERMEZZO If you would like more information talk with your doctor You can ask your doctor or pharmacist for information about INTERMEZZO that is written for healthcare professionals For more information about INTERMEZZO call Purdue Pharma at 1-888-726-7535 or go to wwwpurduepharmacom or wwwintermezzorxcom

What are the ingredients in INTERMEZZO

Active Ingredient Zolpidem tartrate

Inactive Ingredients Each INTERMEZZO tablet includes the following inactive ingredients mannitol sorbitol crospovidone silicon dioxide sodium carbonate sodium bicarbonate croscarmellose sodium sodium stearyl fumarate silicon dioxide natural and artificial spearmint flavor silicon dioxide-colloidal and sucralose The 175 mg tablet also contains yellow iron oxide and the 35 mg tablet contains beige iron oxide

Rx only

This Medication Guide has been approved by the US Food and Drug Administration

Distributed by Purdue Pharma LP Stamford CT 06901-3431

Issued August 2019


Instructions for Use

INTERMEZZOreg (in ter meacutet zoh)


Read these Instructions for Use before you start taking INTERMEZZO and each time you get a refill There may be new information This information does not take the place of talking to your healthcare provider about your medical condition or your treatment

What is the most important Information I should know about INTERMEZZO

Follow these Instructions for Use when you take INTERMEZZO If you do not follow these instructions you might be drowsy in the morning without knowing it

bull Only take 1 tablet a night if needed bull Only take INTERMEZZO if you have at least 4 hours of bedtime left

Using INTERMEZZO the wrong way can make you drowsy in the morning

Before you go to bed

bull Place only 1 INTERMEZZO pouch by your bed and have a clock or watch nearby (see Figure A)

Figure A

bull Store all other unopened INTERMEZZO pouches with your other medicines away from your bedside

bull Only open the INTERMEZZO pouch when you are ready to use it

bull You can either use the INTERMEZZO Dosing Time Chart (see Figure B) or the Dosing Time Tool (see Figure C) that comes with INTERMEZZO to find the latest time during the night you can take INTERMEZZO

INTERMEZZO Dosing Time Chart (see Figure B)

bull You can take INTERMEZZO if you have at least 4 hours of bedtime left before you must be awake


bull Find the earliest time you have to be up and awake in the column on the left

bull Find the latest time you can take INTERMEZZO on the same line in the column on the right

INTERMEZZO Dosing Time Chart

If you must Take be awake by INTERMEZZO before

4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B

INTERMEZZO Dosing Time Tool (see Figure C) bull Turn the INTERMEZZO Dosing Time Tool wheel to show the earliest time that you

must be awake under the green arrow

bull Take INTERMEZZO before the time under the brown arrow

Figure C

During the night when you take INTERMEZZO

Step 1 Check the current time and use the INTERMEZZO Dosing Time Chart or the INTERMEZZO Dosing Time Tool to decide if you should take INTERMEZZO

bull Only take INTERMEZZO if you have at least 4 hours of bedtime left before you have to be awake (see Figure B)

Step 2 Open the INTERMEZZO pouch you placed by your bed


bull Fold the INTERMEZZO pouch along the dotted line While the INTERMEZZO pouch is folded tear the pouch open at the notch at the center of the dotted line (see Figure D)

Figure D

Step 3 Remove the tablet from the INTERMEZZO pouch

Step 4 Leave the empty INTERMEZZO pouch where you can see it The empty pouch will help remind you that you already took your INTERMEZZO dose (see Figure E)

Figure E

Step 5 While in bed place the INTERMEZZO tablet under your tongue and allow it to break apart completely then swallow Do not swallow it whole (see Figure F)

Figure F


Step 6 Throw the empty INTERMEZZO pouch away in the morning

When you wake up in the morning be sure that at least 4 hours have passed since you have taken INTERMEZZO and you feel fully awake before driving Do not do dangerous activities until you know how INTERMEZZO affects you

This Medication Guide and Instructions for Use have been approved by the US Food and Drug Administration


Issued 082019


FULL PRESCRIBING INFORMATION CONTENTS WARNING COMPLEX SLEEP BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

21 Important Administration Instructions 22 Basic Dosing Information 23 Use with CNS Depressants 24 Use in Geriatric Patients 25 Use in Patients with Hepatic Impairment

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

51 Complex Sleep Behaviors 52 CNS Depressant Effects and Next-Day Impairment 53 Need to Evaluate for Co-Morbid Diagnoses 54 Severe Anaphylactic and Anaphylactoid Reactions 55 Abnormal Thinking and Behavioral Changes 56 Use in Patients with Depression 57 Respiratory Depression 58 Withdrawal Effects

6 ADVERSE REACTIONS 61 Clinical Trials Experience

7 DRUG INTERACTIONS 71 CNS-active Drugs 72 Drugs that Affect Drug Metabolism via Cytochrome P450


81 Pregnancy 83 Nursing Mothers 84 Pediatric Use 85 Geriatric Use 86 Gender Differences in Pharmacokinetics

9 DRUG ABUSE AND DEPENDENCE 91 Controlled Substance 92 Abuse 93 Dependence

10 OVERDOSAGE 101 Signs and Symptoms 102 Recommended Treatment

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

121 Mechanism of Action 123 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 131 Carcinogenesis Mutagenesis Impairment of Fertility

14 CLINICAL STUDIES 141 Middle-of-the-Night Awakening Trials 142 Special Safety Studies

16 HOW SUPPLIEDSTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the Full Prescribing Information are not listed

















































INTERMEZZO (n=150)

Placebo (n=145)



Fatigue 1 0



7 DRUG INTERACTIONS


Imipramine


Haloperidol


Alcohol


Sertraline


Fluoxetine



Rifampin


Ketoconazole


















Placebo

Dizziness 3 0

Drowsiness 5 2

Diarrhea 3 1















10 OVERDOSAGE







N

N

CH3

O

N

CH3

CH3

CH3

OHOH

O

OH

OH

O

2











Distribution


Metabolism


Elimination



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019

















































INTERMEZZO (n=150)

Placebo (n=145)



Fatigue 1 0



7 DRUG INTERACTIONS


Imipramine


Haloperidol


Alcohol


Sertraline


Fluoxetine



Rifampin


Ketoconazole


















Placebo

Dizziness 3 0

Drowsiness 5 2

Diarrhea 3 1















10 OVERDOSAGE







N

N

CH3

O

N

CH3

CH3

CH3

OHOH

O

OH

OH

O

2











Distribution


Metabolism


Elimination



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019


7 DRUG INTERACTIONS


Imipramine


Haloperidol


Alcohol


Sertraline


Fluoxetine



Rifampin


Ketoconazole


















Placebo

Dizziness 3 0

Drowsiness 5 2

Diarrhea 3 1















10 OVERDOSAGE







N

N

CH3

O

N

CH3

CH3

CH3

OHOH

O

OH

OH

O

2











Distribution


Metabolism


Elimination



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019

















Placebo

Dizziness 3 0

Drowsiness 5 2

Diarrhea 3 1















10 OVERDOSAGE







N

N

CH3

O

N

CH3

CH3

CH3

OHOH

O

OH

OH

O

2











Distribution


Metabolism


Elimination



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019











10 OVERDOSAGE







N

N

CH3

O

N

CH3

CH3

CH3

OHOH

O

OH

OH

O

2











Distribution


Metabolism


Elimination



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019










Distribution


Metabolism


Elimination



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019



Special Populations




Drug Interactions

CNS-depressants






















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019



















14 CLINICAL STUDIES











Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019





Rebound effects






















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019


















Suicide









MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019


MEDICATION GUIDE















o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019






o having sex

o sleep-walking


Important





What is INTERMEZZO


































bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019



























bull memory loss

bull anxiety




bull Headache

bull Nausea

bull Fatigue















Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019






Rx only



Issued August 2019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019












Figure A











4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019






4 am 12 midnight

5 am 1 am

6 am 2 am

7 am 3 am

8 am 4 am

9 am 5 am Figure B




Figure C







Figure D



Figure E


Figure F






Issued 082019



Figure D



Figure E


Figure F






Issued 082019






Issued 082019


HIGHLIGHTS OF PRESCRIBING INFORMATION ... · INTERMEZZO and of other concomitant CNS depressants...

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Transcript of HIGHLIGHTS OF PRESCRIBING INFORMATION ... · INTERMEZZO and of other concomitant CNS depressants...